This is a nationalization of PCT/EP00/03388 filed Apr. 14, 2000 and published in English.
The invention relates to novel compounds which are used in the pharmaceutical industry as active compounds for the production of medicaments.
U.S. Pat. No. 4,468,400 describes tricyclic imidazo[1,2-a]pyridines having various ring systems fused to the imidazopyridine parent structure, which are intended to be suitable for the treatment of peptic ulcers.xe2x80x94International Patent Application WO98/42707 discloses tetrahydroimidazonaphthyridines having a very specific substitution pattern, which are likewise intended to be suitable for the treatment of gastric and intestinal disorders.
The invention relates to compounds of the formula I 
in which
R1 is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl,
R2 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl or 2-4C-alkynyl,
R3 is hydrogen, halogen, trifluoromethyl, 1-4C-alkyl, 2-4C-alkenyl or 2-4C-alkynyl,
one of the substituents R4a and R4b is hydrogen and the other is hydrogen, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy or the radical R4xe2x80x2, or in which R4a and R4b together are O (oxygen),
xe2x80x83where R4xe2x80x2 is 1-4C-alkoxy which is completely or mainly substituted by halogen,
one of the substituents R5a and R5b is hydrogen and the other is hydrogen, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy or the radical R5xe2x80x2, or in which R5a and R5b together are O (oxygen),
xe2x80x83where R5xe2x80x2 is 1-4C-alkoxy which is completely or mainly substituted by halogen,
where one of the substituents R4a and R4b must have the meaning R4xe2x80x2 and/or one of the substituents R5a and R5b must have the meaning R5xe2x80x2,
or in which
one of the substituents R4a and R4b on the one hand and one of the substituents R5a and R5b on the other hand in each case is hydrogen, and the other substituents in each case together form a 1-2C-alkylenedioxy radical which is completely or partially substituted by halogen,
R6 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or trifluoromethyl and
R7 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,
and their salts.
1-4C-alkyl represents strain-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radical.
Hydroxy-1-4C-alkyl represents abovementioned 1-4C-alkyl radicals which are substituted by a hydroxyl group. Examples which may be mentioned are the hydroxymethyl, the 2-hydroxyethyl and the 3-hydroxypropyl radical.
Halogen within the meaning of the invention is bromine, chlorine or fluorine.
2-4C-alkenyl represents straight-chain or branched alkenyl radicals having 2 to 4 carbon atoms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl and the 2-propenyl radical (allyl radical).
2-4C-alkynyl represents straight-chain or branched alkynyl radicals having 2 to 4 carbon atoms. Examples which may be mentioned are the 2-butynyl, 3-butynyl and preferably the 2-propynyl radical (propargyl radical).
1-4C-alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radical.
1-4C-alkoxy-1-4C-alkoxy represents one of the abovementioned 1-4C-alkoxy radicals which is substituted by a further 1-4C-alkoxy radical. Examples which may be mentioned are the radicals 2-methoxyethoxy (CH3xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94) and 2-ethoxyethoxy (CH3xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94).
1-4C-alkylcarbonyl represents a radical which, in addition to the carbonyl group, contains one of the abovementioned 1-4C-alkyl radicals. An example which may be mentioned is the acetyl radical.
1-4C-alkylcarbonyloxy represents a 1-4C-alkylcarbonyl group which is bonded to an oxygen atom. An example which may be mentioned is the acetoxy radical (CH3COxe2x80x94Oxe2x80x94).
Completely or mainly halogen-substituted 1-4C-alkoxy which may be primarily mentioned are chlorine and/or, in particular, fluorine-substituted 1-4C-alkoxy radicals. Examples of halogen-substituted 1-4C-alkoxy which may be mentioned are the 2,2,2-trichloroethoxy, the hexachloroisopropoxy, the pentachloroisopropoxy, the 1,1,1-trichloro-3,3,3-trifluoro-2-propoxy, the 1,1,1-trichloro-2-methyl-2-propoxy, the 1,1,1-trichloro-2-propoxy, the 3-bromo-1,1,1-trifluoro-2-propoxy, the 3-bromo-1,1,1-trifluoro-2-butoxy, the 4-bromo-3,3,4,4-tetrafluoro-1-butoxy, the chlorodifluoromethoxy, the 1,1,1,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1,1,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4-heptafluoro-1-butoxy, the 4,4,4-trifluoro-1-butoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy radical.
Completely or partially halogen-substituted 1-2C-alkylenedioxy which may be mentioned in particular are fluorine-substituted 1-2C-alkylenedioxy, for example the difluoroethylenedioxy (xe2x80x94Oxe2x80x94CF2xe2x80x94CH2xe2x80x94Oxe2x80x94), the tetrafluoroethylenedioxy (xe2x80x94Oxe2x80x94CF2xe2x80x94CF2xe2x80x94Oxe2x80x94) and in particular the difluoromethylenedioxy (xe2x80x94Oxe2x80x94CF2xe2x80x94Oxe2x80x94), and the 1,1,2-trifluoroethylenedioxy radical (xe2x80x94Oxe2x80x94CF2CHFxe2x80x94Oxe2x80x94) and also the chlorotrifluoroethylenedioxy radical.
1-4C-alkoxycarbonyl represents a carbonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded. Examples which may be mentioned are the methoxycarbonyl (CH3Oxe2x80x94C(O)xe2x80x94) and the ethoxycarbonyl radical (CH3CH2Oxe2x80x94C(O)xe2x80x94).
1-4C-alkoxycarbonylamino represents an amino radical which is substituted by one of the abovementioned 1-4C-alkoxycarbonyl radicals. Examples which may be mentioned are the ethoxycarbonylamino and the methoxycarbonylamino radical.
1-4C-alkoxy-1-4C-alkoxycarbonyl represents a carbonyl group to which one of the abovementioned 1-4C-alkoxy-1-4C-alkoxy radicals is bonded. Examples which may be mentioned are the 2-methoxyethoxycarbonyl(CH3xe2x80x94Oxe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94) and the 2-ethoxyethoxycarbonyl radical (CH3CH2xe2x80x94Oxe2x80x94CH2CH2xe2x80x94Oxe2x80x94COxe2x80x94).
1-4C-alkoxy-1-4C-alkoxycarbonylamino represents an amino radical which is substituted by one of the abovementioned 1-4C-alkoxy-1-4C-alkoxycarbonyl radicals. Examples which may be mentioned are the 2-methoxyethoxycarbonylamino and der 2-ethoxyethoxycarbonylamino radical.
Possible salts of compounds of the formula Ixe2x80x94depending on substitutionxe2x80x94are especially all acid addition salts. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids customarily used in pharmacy. Those which are suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are employed in salt preparationxe2x80x94depending on whether it is a mono- or polybasic acid and depending on which salt is desiredxe2x80x94in an equimolar quantitative ratio or one differing therefrom.
Pharmacologically intolerable salts, which can be initially obtained, for example, as process products in the preparation of the compounds according to the invention on the industrial scale, are converted into pharmacologically tolerable salts by processes known to the person skilled in the art.
It is known to the person skilled in the art that the compounds according to the invention and their salts can contain various amounts of solvents if they are isolated, for example, in crystalline form. The invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula I, and all solvates and in particular all hydrates of the salts of the compounds of the formula I.
The compounds of the formula I have at least two chiral centers. The invention relates to all conceivable stereoisomers in any desired mixing ratio to one another, including the pure enantiomers, which are a preferred subject of the invention.
An exemplary preferred radical R1 is the methyl radical.
Exemplary preferred radicals R2 are the methyl and the hydroxymethyl radical.
R3 in the context of the present invention is preferably hydrogen.
Compounds worthy of mention are those of the formula I, in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl or hydroxy-1-4C-alkyl,
R3 is hydrogen,
one of the substituents R4a and R4b is hydrogen and the other is hydrogen, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or the radical R4xe2x80x2,
xe2x80x83where
R4xe2x80x2 is completely or mainly halogen-substituted halogen-substituted 1-4C-alkoxy, one of the substituents R5a and R5b is hydrogen and the other is hydrogen, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or the radical R5xe2x80x2,
xe2x80x83where
R5xe2x80x2 is completely or mainly halogen-substituted 1-4C-alkoxy,
where one of the substituents R4a and R4b must have the meaning R4xe2x80x2 and/or one of the substituents
R5a and R5b must have the meaning R5xe2x80x2,
or in which
one of the substituents R4a and R4b on the one hand and one of the substituents R5a and R5b on the other hand is in each case hydrogen, and the other substituents in each case together form a completely or partially halogen-substituted 1-2C-alkylenedioxy radical,
R6 is hydrogen, halogen or trifluoromethyl and
R7 is hydrogen or halogen,
and their salts.
Compounds of the invention to be emphasized are those of the formula I* 
in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl or hydroxy-1-4C-alkyl,
R3 is hydrogen,
one of the substituents R4a and R4b is hydrogen and the other is hydrogen, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or the radical R4xe2x80x2,
xe2x80x83where
R4xe2x80x2 is completely or mainly fluorine-substituted 1-4C-alkoxy or chlorodifluoromethoxy,
one of the substituents R5a and R5b is hydrogen and the other is hydrogen, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or the radical R5xe2x80x2,
xe2x80x83where
R5xe2x80x2 is completely or mainly fluorine-substituted 1-4C-alkoxy or chlorodifluoromethoxy,
where one of the substituents R4a and R4b must have the meaning R4xe2x80x2 and/or one of the substituents
R5a and R5b must have the meaning R5xe2x80x2,
or in which
one of the substituents R4a and R4b on the one hand and one of the substituents R5a and R5b on the other hand is in each case hydrogen, and the other substituents in each case together form a completely or partially fluorine-substituted 1-2C-alkylenedioxy radical or chlorotrifluoroethylenedioxy radical,
R6 is hydrogen, halogen or trifluoromethyl and
R7 is hydrogen or halogen,
and their salts.
An embodiment (embodiment a) of the compounds of the formula I* to be emphasized is that in which one of the substituents R4a and R4b is hydrogen and the other is the radical R4xe2x80x2 and one of the substituents R5a and R5b is hydrogen and the other is hydroxyl.
A further embodiment (embodiment b) of the compounds of the formula I* to be emphasized is that in which
one of the substituents R4a and R4b is hydrogen and the other is the radical R4xe2x80x2 and
one of the substituents R5a and R5b is hydrogen and the other is 1-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy.
A further embodiment (embodiment c) of the compounds of the formula I* to be emphasized is that in which
one of the substituents R4a and R4b is hydrogen and the other is the radical R4xe2x80x2 and
one of the substituents R5a and R5b is hydrogen and the other is the radical R5xe2x80x2.
A further embodiment (embodiment d) of the compounds of the formula I* to be emphasized is that in which
one of the substituents R4a and R4b is hydrogen and the other is 1-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy and one of the substituents R5a and R5b is hydrogen and the other is the radical R5xe2x80x2.
Compounds I* of embodiments a, b, c and d particularly to be emphasized are those in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 is hydrogen,
R4xe2x80x2 is completely or mainly fluorine-substituted 1-4C-alkoxy or chlorodifluoromethoxy,
R5xe2x80x2 is completely or mainly fluorine-substituted 1-4C-alkoxy or chlorodifluoromethoxy,
R6 is hydrogen and
R7 is hydrogen,
and their salts.
Preferred compounds I* of embodiment a are those in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 is hydrogen,
one of the substituents R4a and R4b is hydrogen and the other is R4xe2x80x2,
where
R4xe2x80x2 is completely or mainly fluorine-substituted 1-4C-alkoxy or chlorodifluoromethoxy,
one of the substituents R5a and R5b is hydrogen and the other is hydroxyl,
R6 is hydrogen and
R7 is hydrogen,
and their salts.
Preferred compounds I* of embodiment b are those in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 is hydrogen,
one of the substituents R4a and R4b is hydrogen and the other is R4xe2x80x2,
where
R4xe2x80x2 is completely or mainly fluorine-substituted 1-4C-alkoxy or chlorodifluoromethoxy,
one of the substituents R5a and R5b is hydrogen and the other is 1-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy,
R6 is hydrogen and
R7 is hydrogen,
and their salts.
Preferred compounds I* of embodiment c are those in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 is hydrogen,
one of the substituents R4a and R4b is hydrogen and the other is R4xe2x80x2,
where
R4xe2x80x2 is completely or mainly fluorine-substituted 1-4C-alkoxy or chlorodifluoromethoxy,
one of the substituents R5a and R5b is hydrogen and the other is R5xe2x80x2,
where
R5xe2x80x2 is completely or mainly fluorine-substituted 1-4C-alkoxy or chlorodifluoromethoxy,
R6 is hydrogen and
R7 is hydrogen,
and their salts.
Preferred compounds I* of embodiment d are those in which
R1 is 1-4C-alkyl,
R2 is 1-C-alkyl,
R3 is hydrogen,
one of the substituents R4a and R4b is hydrogen and the other is 1-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy,
one of the substituents R5a and R5b is hydrogen and the other is R5xe2x80x2,
where
R5xe2x80x2 is completely or mainly fluorine-substituted 1-4C-alkoxy or chlorodifluoromethoxy,
R6 is hydrogen and
R7 is hydrogen,
and their salts.
Selected preferred compounds I* are those of embodiments a, b, c and d in which R5b is hydrogen.
Selected particularly preferred compounds I* are those of embodiments a, b, c and d in which R5b is hydrogen and R4a is hydrogen.
Selected preferred radicals R4xe2x80x2 and R5xe2x80x2 are the 2,2,2-trifluoroethoxy- and the difluoromethoxy radical.
The following exemplary selected preferred compounds according to the invention may be explicitly mentioned with the aid of formula I** below with the substituent meanings for R4a, R4b and R5a in the following Table 1 (Tab. 1): 
The compounds according to the invention are prepared, for example, starting from the compounds of the formula I disclosed in WO98/42707, in which at least one of the substituents R4a, R4b, R5a and R5b has the meaning hydroxyl (subsequently called xe2x80x9cstarting compoundsxe2x80x9d). Starting from these starting compounds, the preparation of the compounds according to the inventionxe2x80x94depending on which final product is desiredxe2x80x94can be carried out in various ways, for example by acid-catalyzed etherification of the starting compounds with compounds of the formula R4xe2x80x2-H or R5xe2x80x2-H, for example as described below.
The substances according to the invention are isolated and purified in a manner known per se, for example by distilling off the solvent in vacuo and recrystallizing the resulting residue from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on suitable support material.
Salts are obtained by dissolving the free compound in a suitable solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid, or to which the desired acid is then added. The salts are obtained by filtering, reprecipitating, precipitating with a nonsolvent for the addition salt or by evaporation of the solvent. Salts obtained can be converted into the free compounds, which in turn can be converted into salts, by alkalization or by acidification. In this way, pharmacologically nontolerable salts can be converted into pharmacologically tolerable salts.
The pure enantiomers, in particular the pure enantiomers of the formula I*, which are a preferred subject of the invention, can be obtained in a manner familiar to the person skilled in the art, for example by enantioselective synthesis, by chromatographic resolution on chiral separating columns, by derivatization with chiral auxiliary reagents, subsequent separation of diastereomers and cleavage of the chiral auxiliary group, by salt formation with chiral acids, subsequent resolution of the salts and liberation of the desired compound from the salt, or by (fractional) crystallization from a suitable solvent.